Objective:

To report a pathway for broader use of individualized allele-specific antisense oligonucleotides through diplotyping

Background:

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to address underlying causes of genetic diseases by altering RNA processing and protein expression. They are engineered to target a patient's particular genetic variant, enabling the development of individualized treatments for rare genetic diseases. Allele-specific ASOs that selectively downregulate the allele containing the deleterious variant responsible for disease via a gain-of-function mechanism have demonstrated clinical efficacy.  A notable example comes from an n-of-1 clinical trial utilizing an individualized, allele-specific ASO that resulted in substantial seizure reduction and improvement in neurodevelopmental in a patient with SCN2A-related disorder (SRD). This ASO targets the mRNA for degradation by binding to the site of a common single nucleotide polymorphism (SNP) located on the same allele as the disease-causing variant. Identifying patients with the appropriate diplotype amenable to this ASO treatment necessitates accurate haplotype phasing of target SNP and disease-causing variant. However, determining phasing accurately is challenging with standard paired-end short-read sequencing.

Design/Methods:

Novel whole genome sequencing (WGS) technology facilitates ultra-long phasing by utilizing cluster proximity information to overcome this limitation. Using this technology to confirm phasing of de novo disease-causing variant and target SNP, we analyzed a cohort of SRD patients to assess potential reach of the ASO therapy.  

Results:

Conclusions:

We demonstrate an innovative approach to broaden use of individualized ASOs. Targeting common SNPs rather than solely disease-causing variants, this offers potential benefits for a wider range of SRD patients and promise for application in other genetic disease.